Polymorphism refers to such a phenomenon that a solid substance in two or more different spatial arrangements forms solid states with different physicochemical properties. In the field of drug research, polymorphs also include multi-component crystal forms of such as organic solvates and hydrates.
The phenomenon of drug polymorphism is widespread in the drug development process and is an inherent characteristic of organic small molecule compounds. In theory, small molecule drugs can have an infinite number of crystal packing modes—polymorphism. Studies have shown that the number of discovered polymorphs of a drug is directly proportional to the time and resources invested in research. For example, Lipitor, the drug with the highest sales in the world, has as many as 35 patented crystal forms.
The polymorphism phenomenon is not only controlled by the intrinsic factors such as the spatial structure and functional group properties of the molecule itself, intramolecular and intermolecular interactions, but also affected by various factors such as drug synthesis process design, crystallization and purification conditions, selection of formulation excipient, process route of formulation and granulating method, storage conditions, and packaging materials. Different crystal forms have different colors, melting points, dissolution performance, chemical stability, reactivity, mechanical stability, etc. These physical and chemical properties or processability sometimes directly affect the safety and effective performance of drugs. Therefore, the research and control of crystal form has become an important research content in the drug development process.
Researches of crystal forms include two stages, discovery of crystal forms and optimization of crystal forms. In the stage of discovering crystal forms, various crystallization methods are mainly used, such as melt crystallization, solution evaporation, rapid cooling, and suspension method, by changing the external factors that affect the crystallization of drugs, such as crystallization conditions, solvent, temperature, speed and proportion of suspended solvents, etc. A high-throughput sample preparation platform is used to process hundreds of crystallization experiments simultaneously, and new crystal forms are prepared and discovered using microsample preparation technology and analytical testing methods. In the stage of optimizing crystal forms, new crystal craft is subjected to amplification and the preparation conditions are to be explored. Various solid characterization methods such as X-ray diffraction, solid-state nuclear magnetic resonance, raman spectroscopy, and infrared spectroscopy are used to characterize the crystal form. In addition, DSC, TGB, DVS, and HPLC, etc. are used to study the physicochemical properties of the crystal forms and compare the hygroscopicity, chemical stability, physical state stability, and processability of different crystal forms. Finally, the most preferred solid form is chosen for the development.
The chemical name of pyrroloquinoline quinine (PQQ) is:
4,5-Dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid, and its chemical structural formula is shown as follows:

PQQ is a newly discovered vitamin B, which is a coenzyme different from the oxidoreductases of pyridine nucleotides and riboflavin. The unique structure of the ortho-quinones makes PQQ unique in its physical and chemical properties and a variety of physiological functions. There is a wide application prospect in food, medicine, agriculture and other industries. PQQ has a polymorphism phenomenon; however, there are no reports of its polymorphism in patent.
A new crystal form of PQQ: crystal form B, is reported in the present invention on the basis of the comprehensive adoption of a new crystallizing nucleation methods and crystallizing conditions.